LEFT VENTRICULAR MASS:Measurement, Significance and

Management in CKD/ESRD

Richard J. Glassock, MD, MACPGeffen School of Medicine at UCLA

ESRD- State-of the ArtBoston

April 23, 2009

20 years after the “Dallas” meeting the overall Annual Mortality rate of Dialysis patients in the USA has

declined by only about 15% and is still highest of all of

the Countries of the Developed World

THEME:

LV Mass in CKD/ESRD as a Paradigm of What is

WRONG with Conventional Regimens of Treatment

LEFT VENTRICULAR MASS in CKD/ESRD

How should it be measured? What are its likely mechanisms? What are its consequences? Can it be reversed (or prevented) by

interventions? What are key management

principles? What are the gaps in knowledge

and directions for future research?

LV Mass in CKD/ESRD

Measurement

LEFT VENTRICULAR MASS:Measurement

Magnetic Resonance Imaging (without contrast)- Gold Standard

Computerized Acoustic Cardiography ; 3D Echocardiography

Echocardiography- 2D Echocardiography-M-mode Serum Troponin-T Serum Atrial and Brain Natriuretic Peptides Electrocardiography (Voltage and Duration-

Voltage Product) Physical examination

INCREASED LV MASSEKG

(Okin PM, et al J. Electrocardiol 29:256, 1996)

0%10%20%30%40%50%60%70%80%90%

100%

Cornell QRSVoltage

Cornell QRSVoltage x

Duration Product

SensitivitySpecificity

LV MASS in ESRD:ANP and BNP

(Mallamaci F, et al KI 59:1559, 2001)

0%

20%

40%

60%

80%

100%

ANP BNP ANP or BNP

Sensitivity SpecificityPositive Predictive Value Negative Predictive Value

INCREASED LV MASS in ESRD:Echocardiography

(Mark P, et al NDT 22:1815, 2007)

M-Mode (1 D), 2 D and 3 D Echocardiography have been commonly used to Quantify LV Mass in ESRD

Volume changes occurring with dialysis can lead to errors in LV Mass estimation by M-Mode/2D Echocardiography (estimates are based on the cube of the LV internal diameter and LVID decreases after HD)

M-Mode and 2D, but not 3D, Echocardiograms overestimate LV Mass, due to asymmetric remodeling in 30% of patients

2D ECHO-Normal(Courtesy- R. Pecoits-Filho, 2009)

2D ECHO- LVH(Courtesy-R. Pecoits-Filho, 2009)

LV MASSEchocardiography (M-Mode or 2D) Echocardiography (M-Mode or 2D)

Normal ValuesNormal Values

Males= <125-130gms/m2 BSA

Females= <100gms/m2 BSA

In Dialysis patients LV Mass should be indexed to Height (gms/m2 or gms/m2.71) rather than BSA due to the weight fluctuations

LV MASS in ESRD:Cardiac Magnetic Resonance Imaging

(CMRI)

Cannot be performed with contrast (gadolinium) in ESRD

Requires at least a 1.5 Tesla magnet Gives LV Mass values about 65gm/m2

greater than M-mode Echocardiography

Pre-post dialysis differences in LV mass with CMRI are less than those found with M-mode Echocardiography (-10gm/m2 vs -26gm/m2)

3D Echocardiography and CMRI give equivalent results for LV Mass

LVH in CKD/ESRD:Measurement-Conclusions

EKG is an insensitive but specific method of diagnosis of increased LV Mass

Troponin-T, ANP and/or BNP levels have excellent positive predictive value for diagnosis of increased LV Mass in ESRD

Cardiac Magnetic Resonance (CMRI) imaging is the “gold-standard” for measuring LV Mass in ESRD

M-Mode Echocardiography overestimates the presence of increased LV Mass (due to volume changes and geometry in ESRD)

LVH in CKD/ESRD:

Epidemiology and “Natural” History during CKD and

Conventional ESRD Therapy

LVH in CKD- ECHOPrevalence of LVH in Non-Diabetic CKD

(Paoletti E, et al AJKJD 46:320, 2005)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Controls Stage 1-2 Stage 3-5

Natural History of LVH in CKD Stages 3/4

(Over two years)(McMahon LP, et al JASN 15:1624, 2004)

CKD (Stage 3/4) ↓

Echocardiography LVH+ LVH- (30%) (70%)

LVH+ LVH- LVH+ LVH- (70%) (30%) (30%) (70%)

LVH in ESRD(London GM, et al JASN 12:2759-2767, 2001)

153 patients receiving “conventional” HD for >9 months followed for average of 54 months (10-126 months) with serial hemodynamic measurements (including ECHO)

Outcome parameters (mortality and CV events) correlated with hemodynamic, hematological and biochemical variables

Response= >10% reduction in LVMI (gms/m2)

Baseline- 90% had LVH

LVH in ESRD(London, et al JASN, 2001)

22%

32%

46%

Regressed No Change Progressed

LV Mass in CKD/ESRD:Epidemiology-Conclusions

LV Mass steadily increase as CKD progresses, but not inevitably

Increased LV Mass in incident ESRD patients is very common (70-90%), but will subsequently regress in only about 50% of patients with conventional HD or PD.

Non-regressors on HD/PD have a poor prognosis

LVH in CKD/ESRD

Mechanisms

Pathogenesis of LVH in CKD/ESRD:Preload, Afterload and Other Factors

(Ritz E. Kidney Int 75:771-773, 2009)

LVH in CKD/ESRD- Pathogenetic Mechanisms

Afterload- (Systemic vascular resistance, SBP, vascular compliance)

Preload- (Intravascular volume, anemia, A-V fistula)

Non-After or –Preload Factors

LVH IN CKD/ESRDLVH IN CKD/ESRD::Non- After or –Preload Factors

Activation of mTOR Intra-cardiac RAS Phosphate retention Markedly elevated PTH levels Vitamin D deficiency Carnitine deficiency SNS Activation Cytokine/Hormone/Catechol

production- (aldosterone, endothelin-1, TNFα, Leptin. Il-1α, Il-6, TGFβ, nor-epinephrine)

Gender

mTOR and LVH in CKD(Siedlecki, et al. KI April, 2009)

A Mouse model of CKD produced by partial surgical nephrectomy (SIRI)

LVH developed in absence of hypertension or volume expansion

ERK and S6 activated (mTOR-dependent TF)

Sirolimus abolished LVH (no effect on BP)

mTOR and LVH(Siedlecki AM, et al, KI January 2009)

0

1

2

3

4

5

6

LVMI (mg/ gm) LV/ Tibial length(mmg/ mm)

RV/ Tibial length(mg/ mm)

SIRI SIRI + Vehicle SIRI + Rapamycin Sham

mTOR and LVH: Post-Renal Transplant

(Paoletti E, et al AJKD 52:324, 2008)

0%

20%

40%

60%

80%

100%

Regression of LVH

CNI to Sirolimus CNI

mTOR Inhibition can ameliorate (or prevent) LVH

in CKD (Independent of BP/Anemia/Volume)- Not yet

tested in ESRD

Vitamin D and LVH in ESRD(Achinger SG and Ayus JC. KI 95:s37, 2005)

Vitamin D deficiency can activate the RAS and promotes secondary hyperparathyroidism– and thus promote LVH and elevated blood pressure.

Retrospective studies have shown regression of

LVH in Vitamin D treated ESRD patients

Experimentally, activated Vitamin D supplements (Paricalcitol) reduce LVH, possibly via an effect on intra-cardiac RAS

Vitamin D use may reduce CVD mortality in ESRD patients (observational data primarily)

No RCT in Humans showing a beneficial effect of Vitamin D supplementation on LVMI in ESRD has yet appeared

Hyperphosphatemia and LVH in ESRD

(Achinger, Ayus, JASN 17:s255, 2006; Strozecki P, et al Ren Fail 23:125, 2001;Galetta F, et al J Intern Med 258:378, 2005)

Correlations between serum phosphorous levels and calcium x phosphorus product and LVH have been repeatedly noted

Causality is not proven (absence of RCT with LVMI as primary end-point)

Daily HD effectively reduces serum Phosphorus levels and also improves LVMI

Parathyroid Hormone and LVH

PTH levels correlate directly with LVH in both primary and secondary hyperparathyroidism (inconsistently)

Parathyroidectomy can cause regression of LVH

PTH (1-34) can induce LVH (via MAPK/ERK activation)

PTH and LVH in ESRD(Fujii H, et al Inter Med. 46:1509, 2007)

020406080

100120140160180200

LVMI (g/ m2)

<300pg/ ml >300pg/ ml >500pg/ ml

PTH Levels

RAAS and LVH in ESRD Angiotensin II directly induces

cardiomyocyte hypertrophy, independent of afterload

Local (intra-cardiac) Angiotensin II is generated by myocardial stretch--But hypertrophy still occurs in AT1b receptor KO mice

Aldosterone (?via TGFβ) may play an Angiotensin II independent role in myocardial fibrosis and LVH

LVH in ESRD:AV Fistula Effects

(in Transplant Recipients)(Cridlig J, et al Transpl Int 21:948, 2008)

0

20

40

60

80

100

120

140

LVMI (gms/ m2)

AVF+AVF-

LVH in CKD/ESRD:Key Factors in Pathogenesis

Degree of Control of Systemic Arterial Resistance and Large Vessel Distensability (Systolic BP, PW Velocity)

Degree of Control of Hypervolemia (Ultrafiltration, Interdialytic weight gain, Interdialytic interval, ?Anemia)

Preload and Afterload Independent Factors (mTOR activation, PTH, P04, Vitamin D, Cardiac RAS)

LVH in CKD/ESRD

Consequences

LVH in ESRD:Effect on Mortality/Morbidity

(Zoccali C, et al. KI 65:1492, 2004)

0%

20%

40%

60%

80%

100%

Cumulative Mortality/CV Events

(% )

Low Middle High

Tertiles of LVMI Change (gm/ m2.7/ month)

All Cause Mortality (3 year)Fatal/ Non-Fatal CV Events (3 year)

LVH in ESRD: Effect on Mortality and CV Events

(London, et al JASN, 2001)

0%

10%

20%

30%

40%

50%

60%

70%

Mortality CV Events

Regression No Regression

LVMI and Mortality in Hemodialysis

(London GM, et al JASN 12L2759-2767, 2001)

A 10% reduction in LVMI in ESRD is associated with a 22% reduction in all-cause and a 28% reduction in CV mortality

A 1 gm decrease in total LVMI equals about a 1% decrease in CV mortality (over 54 months of follow-up)

LVH in ESRD(London, et al JASN 2001)

-20%

-10%

0%

10%

20%

30%

SBP PWV Hemoglobin

Regression No Regression

LVH in CKD/ESRD: Cardiovascular Consequences

Cardiovascular events and death > Sudden Cardiac Death

(ventricular arrhythmias) > Dilated Cardiomyopathy and

Congestive Heart Failure > Aggravation of Ischemic Heart

Disease (acute myocardial infarction) > Stroke

(hemorrhagic/thrombotic/ischemic)

CARDIAC DEATHS (n=270):4 D Trial

0%

10%

20%

30%

40%

50%

60%

Sudden Death Acute Myocardial I nfarctionCongestive Heart Failure Other

LEFT VENTRICULAR HYPERTROPHY-4 Year Risk of Sudden Death

(EKG-QRS Criteria)(4 D Trial- Krane V, et al CJASN 4:394, 2009)

0%

5%

10%

15%

20%

25%

30%

LVH Present LVH Absent

NT-pro-BNP and Sudden Death(4-D Trial; Winkler K, et al. Euro Heart J 29:2092, 2008)

0%

5%

10%

15%

20%

25%

30%

1 2 3 4

Quartile of NT-pro-BNP (pg/ ml

LVH IN ESRD:Consequences-Conclusions

Sudden Cardiac Death is the principal consequence of increased LV Mass, most likely due to enhanced risk of fatal ventricular arrhythmias (electrical remodeling-arrythmogenic hypertrophy/fibrosis)

Systolic and/or Diastolic Dysfunction due to cardio-myocyte apoptosis, myosin isoform switch, energy dysmetabolism. Myofilament slippage and fibrosis also contribute to the risk of congestive heart failure (dilated cardiomyopathy)

LVH in CKD/ESRD

COMMON

DANGEROUS

TREATABLE/PREVENTABLE?

LVH in CKD/ESRD-

Effects of Some Interventions

LVH in ESRD:Effect of EPO therapy

Seven (7) RCT have been conducted that examine the effect of EPO therapy on LVH in CKD/ESRD

All but one have failed to show any beneficial effect on LVH of EPO therapy and correction of hemoglobin to normal or near normal levels

EPO Therapy in CKD/ESRD and LVMI:

A Meta-Analysis(Parfrey PS, et al CJASN 4:755-762, 2009)

15 unique, non-overlapping studies involving 1731 subjects (5 of which were RCT)

Effect of EPO on LVMI examined in those with severe anemia (Hemoglobin <10gm/dl) and those with more moderate anemia (Hemoglobin >10<12 gm/dL) at baseline and according to target Hemoglobin (lower=≤12gm/dl and higher= >12gms/dL)

EPO in CKD/ESRD- Change in LVMI: A Meta-Analysis

-40

-30

-20

-10

0

10

Effect Size (change in

LVMI in gm/ m2)

Category

Severe anemia; lower targetModerate anemia; lower targetModerate anemai; higher target

LVH and ESRD:Dialysis mode and Prescription

Observational (cross-sectional) studies have shown a lower prevalence of LVH in PD compared to conventional HD patients (?effect of residual confounding; ?better BP/Volume control; ?AV fistula absence)

More Frequent/Longer HD sessions are strongly associated with a much lower prevalence of LVH (?better volume and PO4 control) compared to conventional HD

LVD in ESRD:HD vs PD

(Tian J-P, et al Ren Fail 30:391, 2008)

0%10%

20%30%40%

50%60%70%

Prevalence of LVH (% )

Hemodialysis Peritoneal Dialysis

LVH in ESRD:Hemodialysis Prescription

One randomized* and one non-randomized** prospective controlled studies have been reported comparing “conventional” (3 x/week) HD with “short-daily” or “nocturnal” HD and evaluating LVH

(* Culleton BF, et al JAMA 298:1291, 2007;**Ayus JC et al JASN 16:2778, 2005)

LVH in ESRD:Nocturnal vs Conventional HD

-8

-6

-4

-2

0

2

4

Change (Baseline to Final)

LVMI SBP PO4 HgB

Nocturnal Conventional

LVH in ESRD:Short Daily vs Conventional HD

(Ayus JC, et al JASN 16:2778, 2005)

-40-35-30

-25-20-15-10

-5

05

LVMI SBP PO4 HgB

Short Daily (n=26) Conventional (n=51)

Frequent Hemodialysis Network Trials

(Suri RS, et al Kidney Int 72:349, 2007)

Two multi-center randomized trials to compare Conventional thrice weekly HD to--

1) Daily in-center HD and (MFD) 2) Nocturanl Home HD (NHHD) Composite Primary End-point – 12

month change in LVMI (by MRI) and SF-36 Physical Health Composite (PHC) scores

LVH in ESRD: “High Flux” vs “Low-Flux”

Hemodialysis

Neither the HEMO Study (NEJM, 2002) nor the MPO Study (JASN, 2009) study stratified for LVMI

We do not know if “High-flux” HD is better than or equivalent to “Low-flux” HD for LVMI.

If low serum albumin (<4.0gm/dL) is associated with an increase in LVMI, then it is possible that “High-flux” HD would be superior (MPO study)

LVH in ESRD:High-flux HD

(Kong CH, et al Bllod Purif 21:163, 2003)

In patients receiving high-flux HD failure to “regress” LVH is associated with:

> Higher inter-dialytic weight gain > persistence of systolic

hypertension > higher PTH levels

LVH in ESRD:Effect of Guideline Adherence

(Covic A, et al J Nephrol 19:783, 2006)

In a prospective (uncontrolled) observational study of 103 patients on HD before and after implementation of EBPG/KDOQI Guidelines—

> 38% had no regression or had further progression of elevated LVMI

> Regression of LVH correlated with improvement of Hgb, PO4 and Ca x Po4 levels (?causality)

LVMI in CKD/ESRD

Key Management Principles

LVH in CKD/ESRD:Key Management Principles- I

Rigorous control of volume overload (diuretics, NaCl restriction, control of inter-dialytic weight gain, ultra-filtration)

Meticulous control of 24 hour blood pressure (targets very uncertain-?120-130/70-80mmHg; ACEi/ARB-(tissue penetrating) preferred; ABPM?

LVH in CKD/ESRD:Key Management Principles- II

Replete Vitamin D Stores (ergocalciferol)

Maintain serum phosphorous at 3.5-5.0mg/dL (diet and PO4 binders)

Maintain iPTH levels <500pg/ml (dialysis)

LVH in CKD/ESRD:Key Management Principles- III

If feasible, use More Frequent Dialysis (nocturnal HD, daily HD)- Favor PD over HD as appropriate (?).

Avoid high-dose EPO- (Maintain HgB >10 gms/dL but <12gm/dL (?); maintain Fe stores

Monitor LVH (LVMI) post-dialysis every 18 months (by 2D ECHO, 3D ECHO or CMRI)

LVH in CKD/ESRD:Key Management Principles-

Uncertainties

Carnitine Supplementation Statins (if CRP elevated and LDL

>120mg/dL) Close AV Fistula (transplant) Convert to Sirolimus from CNI

(transplant) Bilateral nephrectomy CAPD instead of HD Use Tropinin-T/ANP and/or BNP levels

to monitor LVH

LVH in CKD/ESRD:Proposed Clinical Targets

Reduce prevalence of LVH (by CMRI or 3D ECHO) to <10-15%

Reduce Prevalence of Sudden Cardiac Death by >50%

LVH in ESRD:Knowledge Gaps/Future Research

Can LVH be prevented by aggressive multi-factorial therapy started early in the course of CKD?- need an RCT

Can progression of LVH to Dilated Cardiomyopathy be prevented by interruption of molecular mechanisms? (e.g. NIX-induced cardio-myocyte apoptosis; inhibition of fibrosis)

What is (are) the nature of the mTOR activator (s) in CKD/ESRD?

Can small molecule, non-toxic, cardio-selective mTOR inhibitors prevent/treat LVH in ESRD (independent of blood pressure)?

Can fatal cardiac arrhythmias (sudden cardiac death) in severe LVH be prevented?

Will MFD ameliorate LVMI increase and improve survival (decrease sudden death)- RCT-Frequent HD Network in Progress

LVH in ESRD: How Important is Inter-

dialytic Weight Gain?

How important is the Inter-dialytic interval?

LVH in CKD/ESRD:CONCLUSIONS

Current “conventional” HD (thrice- weekly, short-duration, long-inter-dialytic interval) regimens are insufficient to fully correct or substantially modify LVH in ESRD (despite “adequate” dialysis dosage)

Longer (slower) HD regimens with a shorter inter-dialytic intervals (MFD/NHHD) may improve LVH (and thereby reduce mortality due to sudden death)

Goals of CKD/ESRD therapy should include modification of LVH as a high priority (including non-afterload/preload related factors)

LVH in CKD/ESRD

COMMON

DANGEROUS

POORLY UNDERSTOOD AND POORLY TREATED IN OUR

CURRENT CKD/ESRD TREATMENT PARADIGMS